The origin, hormonal nature, and action of hepatotrophic substances in portal venous blood.

Abstract

SUMMARY The origin of hepatotrophic factors in splanchnic venous blood was investigated by modifyingthe portal venous inflow to different parts of the canine liver while leaving the arterial bloodsupply and biliary drainage intact.In one variety of experiment, termed partial transposition, the liver portion perfused with thetotal splanchnic venous blood underwent weight gain and hepatocyte hypertrophy, hyperplasia,and glycogenation compared with the portion perfused with venous blood from thehindquarters, kidneys, and adrenal glands, but the combined weight of the total liver remainedconstant in spite of the rapidly evolving regional disproportions. The lobar changes were welldeveloped within one to two months. At this time, the hepatic lobes supplied with splanchnicvenous blood had higher concentrations of glucokinase and lower concentrations of cyclic 3 ′,5′-adenosine monophosphate and active phosphorylase than the lobes receiving hindlimb andadrenorenal venous blood, indicating that the biochemical environment of the different liverregions was drastically different by virtue of being under specific hormonal control.The dissociation was even more dramatically illustrated by dynamic studies in which thedestruction of cyclic 3 ′, 5′-adenosine monophosphate by phosphodiesterase was blocked withaminophylline thereby permitting estimation of the rate of formation of cyclic 3 ′, 5′-adenosinemonophosphate. In addition, the modifying effect of tolbutamide-induced endogenous insulinupon exogenously administered glucagon was evaluated by serial determinations of cyclic 3 ′,5′-adenosine monophosphate. These investigations with the aminophylline and tolbutamide-glucagon tests demonstrated the anabolic role of insulin and the opposing roles of bothglucagon and epinephrine in contributing to liver homeostasis. Epinephrine and glucagoncaused striking increases in cyclic 3′, 5′-adenosine monophosphate, and insulin had theconverse effect.Another type of preparation involving partition of the splanchnic venous blood between theliver portions was termed splanchnic flow division. The substances responsible for the hepatichypertrophy, hyperplasia, glycogenation, and weight gain were shown to emanate mainly, ifnot virtually exclusively, from the pancreatic-gastroduodenal-splenic venous drainage. Incontrast, intestinal nutritional substrate and hormones from the intestine or adrenal gland werenot profoundly influential in either promoting or preventing the morphologic or glycogenconcentration changes. The concentrations of cyclic 3′, 5′-adenosine monophosphate,phosphorylase, and glucokinase in the two sides of the liver did not follow as distinctive apattern as in the partial transposition experiments. However, the aminophylline andtolbutamide-glucagon tests revealed the same type of major dissociation of cyclic 3′, 5′-adenosine monophosphate as with the partial transpositions. Particularly impressive was theway in which trace doses of tolbutamide-induced endogenous insulin on the side nourished bypancreatic venous blood restrained the cyclic 3′, 5′-adenosine monophosphate response toexogenous glucagon, whereas the other liver fragment which was not so covered by insulinhad completely uninhibited rises in cyclic 3′, 5′-adenosine monophosphate.The conclusion from these experiments is that the hepatotrophic factors previously reportedfrom our laboratories and by other investigators to be in splanchnic venous blood are pancreatichormones and specifically insulin and glucagon. Of these, insulin is anabolic and glucagon ismainly catabolic but not exclusively so, since glucagon also has the anabolic effect ofstimulating gluconeogenesis. The insulin-glucagon relationship and the interrelationship ofthese hormones to others, such as epinephrine, in the moment to moment regulation of nutrient